The invention relates to polyimide carrier matrices, a method of manufacturing the articles and to their use.
Methods for the manufacture of particulate carrier matrices (membranes) with different separating profiles are known and commercially available on the basis of various polymers. Methods for their manufacture are known to the person skilled in the art and are based in practice on basic principles which will be shortly described below:
Preformed polymers preferably of natural or semi-synthetic origin which already have chemical functions for the attachment of ligands, are dissolved in an aqueous solvent. The solution is dispersed in a liquid which is not mixable with this polymer solution. The solution droplets are then solidified for example by netting or other chemical or physical processes to form micro-particles.
Under these conditions, the polymer solution is transformed to spherical solution droplets by dispersion in a non-mixable organic medium in a simple manner. Basic conditions for the application of this basic procedure are good dispersion capability of the polymer solution possibly supported by surface active substances in the dispersion medium. The applicability is therefore limited to the dispersion of aqueous polymer solutions in a hydrophobic organic dispersion medium or, respectively, in a chlorinated hydrocarbon; consequently, only water soluble polymers can be used as matrix former. With additives and the kind of solidification, the pore profile of the support matrix so made or, respectively, the microparticles can be affected but the often required coarse pore structure with high pore density at the particle surface is not obtained.
Furthermore, basically gel-like support matrices are formed whose pore structure is formed exclusively by swelling of the particle. Permanently porous support matrices can basically not be manufactured by this method. Depending on the amount of fixation, highly swelled and therefore easily deformable matrices are formed which are compressed when subjected to economical high flow passage rates and then have a high flow resistance. The use of low-swelling synthetic polymers which are preferably soluble in polar or aprotic solvents is not possible with this method because of the unfavorable mixing conditions with dispersing systems although interesting property profiles can be expected. Examples of support matrices which are manufactured in accordance with the principle, are Sepharose-types TM (preferably manufactured from netted Agarose) and cellulose beads.
A second basic method is based on the use of chemically different, usually hydrophobic, monomers which can be polymerized and which are dispersed together with a polymerization initiator and with additives (chemically very different, organo-soluble, but water insoluble substances) in a non-mixable liquid, preferably water, possibly with the addition of surface active compounds. The monomer/addition-droplets of the dispersions formed in the process are subsequently solidified by a netted precipitation polymerization thereby forming microparticles. During this precipitation polymerization process generally permanent porous support matrices of synthetic netted polymers with little swelling are formed in aqueous media. Characteristic is that the polymer is built in the process of the particle manufacture. Many possibilities of influencing the porosity of the microparticles formed are described in the literature. In a special embodiment, the dispersed droplets of the organic phase are solidified before the polymerization and polymerized in that state.
The second basic method for the manufacture of support matrices however is not applicable if polymers, which have already been synthesized, are to be formed into microparticles. In accordance with this dispersion principle organo-soluble monomers with hydroxyl- amino- and/or carboxyl functions must be selected which significantly limits the content of chemical functions for the binding of affinity ligands. For generating or, respectively increasing, the binding functions capable of coupling, such carrier matrices must be provided, before the application, with corresponding chemical functions to make binding functions available in sufficient quantities. This again requires often the use of aggressive media and harsh after treatment conditions.
Finally, a third basic process is known whereby microparticles can be produced from polymer solutions in analogy to a thermal phase inversion during the formation of the membrane. For realizing this basic process, a solvent mixture and a suitable dispersion medium must be found which corresponds to the described behavior. To this end, from the polymer to be deformed a polymer solution is formed at a raised temperature wherein, upon controlled cooling to room temperature, the polymer solution is subject to a phase inversion. When such a polymer solution is dispersed in a phase-forming dispersion medium (micro-droplet formation) and the dispersion is subsequently cooled, a fixed, generally porous, micro-particle is formed.
In principle, it should be possible to form in accordance with this third basic process low-swell carrier matrices of synthetic polymers and, dependent on the polymer used, chemical groups which can be functionalized. It is however a disadvantage of this third basic process that it is difficult to control the process so as to obtain particles of the respective particle size and to find corresponding solution/dispersion systems. Furthermore, the formed particles have an outer surface with relatively little porosity. The pore inlets have a small pore diameter which makes it difficult for large-volume molecules to enter the particles.
Such particles therefore have little adsorption capacity for large molecule volume substances in spite of a relatively large inner surface.
In all these manufacturing methods, an interface area is established between the particles being formed and the liquid or gaseous surrounding area which, for energetic reasons, changes the surface of the particle being formed in such a way that a surface layer of little porosity, that is with a small number of pores and small pore sizes, is established. The interface layer limits the accessibility of the inner pore system of the particles. By swelling of the whole particle (utilization of the basic principle 1) the surface porosity can be moderately, but not sufficiently, increased which however brings along the disadvantage of a compression instability of the carrier matrix with the passage of a liquid.
Carrier matrices of synthetic organic polymers can be manufactured in accordance with the earlier presentation only conditionally in accordance with the third basic method, if, for dissolving the polymer forming the carrier matrix, polar aprotic solvents or mixtures of such solvents must be used. Suitable solvents can be formed but not suitable dispersion media. Still, if a sufficient number of groups of the polymers to be formed into particles which can be functionalized is present, which however is not necessarily true particularly in connection with these polymers, there is the above described disadvantage of a small surface porosity. This is particularly grave if, like in the immune-adsorption, large-volume molecules are to be removed from the medium by adsorption on a suitable functionalized carrier matrix.
It is furthermore known that polyimides can be chemically changed by amine modification. EP-A 0 401 005 describes the use of amine modifications for the netting of polyimide gas separation membranes in a heterogeneous reaction. In DE-A 41 175 01, the modification of polyimide solutions with amine modifications utilizing a homogeneous reaction in order to increase the viscosity of the polyimide significantly is described. Patents of the Applicants disclose methods of functionalizing polyimides in homogeneous (DE-A 101 11 663) and in heterogeneous (DE-A 101 11 665) reactions, which are so performed that, in both cases, a controllable, particularly a large, number of freely available chemical functions is obtained which can be used for adsorption separations in that form or after further conversions.
The state of the art concerning the presently available matrices is presented in a publication by Suoeka (Present status of apheresis technologies, Part 3: Adsorbents, Therapeutic Apheresis 1 (1997) 271-283). Applications of particular carriers in the chromatography are discussed by Hermanson et al. (Immobilized Affinity Ligand Techniques, Academic Press Inc., San Diego, New York, Boston, London, Sidney, Tokyo, Toronto, 1992, pp. 1-50). Newest developments of carrier matrices are furthermore discussed extensively in a publication by Leonard (New packing materials for protein chromatography, J. Chromatog. B 699 [1997], 3-27.
It is the object of the present invention to provide low-swell, highly porous microparticles with a high surface porosity and a large pore diameter for retaining large-volume molecules with high selectivity, speed and capacity, and a method for the manufacture thereof.